Angiotensin converting enzyme and the arrhythmogenic action of angiotensin I: cardiac cell membrane as a site of angiotensin I conversion

The influence of angiotensin I (Ang I) on heart excitability and refractoriness was investigated in isolated right ventricular muscle of adult rats as well as in isolated ventricular myocytes. The results indicated that Ang I (10(-8) M) added to the bath solution, decreased the action potential duration from 50.4 +/- 3.6 to 33.9 +/- 3.9 ms (P < 0.05) and reduced significantly the cardiac refractoriness. Consequently, a discharge of spontaneous action potentials was elicited when a second stimulus was applied during the relative refractory period. Moreover, the conduction velocity was reduced from 56.9 +/- 2.9 to 40 +/- 3.2 cm/s (P < 0.05). The question whether the effect of Ang I was related to its conversion to Ang II, was investigated on tissues exposed to enalapril maleate (10(-8) M). Under these conditions, the effect of Ang I was totally suppressed. Similar results were found with losartan (10(-7) M). To investigate if the conversion of Ang I to Ang II occurs at the level of surface cell membrane. measurements of inward calcium current (I-Ca) were performed in myocytes isolated from the rat ventricle. I-Ca was measured before and after the administration of Ang I (10(-8) M). The results indicated that Ang I (10(-8) M), added to the bath solution, reduced the peak I-Ca density by 26.3 +/- 2.6% (P < 0.05), an effect abolished by enalapril maleate (10(-8) M). Conclusion: Evidence is presented for the first time, that Ang I is converted to Ang II at the surface cell membrane in cardiac muscle with consequent generation of cardiac arrhythmias which are elicited by Ang II. (C) 2004 Published by Elsevier B.V.